Vildagliptin, a dipeptidyl peptidase-4 inhibitor, reduces betel-nut induced carcinogenesis in female mice.

Moumita Nath, Kasturi Bhattacharjee, Yashmin Choudhury

Life sciences 2021 Feb 01

filter terms:

Betel-nut, a popular masticatory among Southeast Asian populations is a class I carcinogen, previously associated with dyslipidemia and aberrant lipid metabolism, and is reported to be used more frequently by females, than males. This study investigates the potential of repurposing the anti-diabetic drug, vildagliptin, a dipeptidyl peptidase-4 inhibitor, for alleviating the oncogenic condition in female Swiss Albino mice administered an aqueous extract of betel-nut (AEBN) orally (2 mg ml-1) for 24 weeks. Tissues were investigated by histopathological, immunohistochemical and apoptosis assays. Biochemical analyses of oxidative stress markers and lipid profile were performed using different tissues and sera. The expressions of different proteins involved in lipid metabolism and oncogenic pathways were evaluated by Western blotting. AEBN induced carcinogenesis primarily in the liver by significantly impairing AMPK signaling, inducing oxidative stress, activating Akt/mTOR signaling, increasing Ki-67 immunoreactivity and cyclin D1 expression, and significantly diminishing apoptosis. Co-administration of AEBN with vildagliptin (10 mg kg-1 body weight) for 8 weeks reduced liver dysplasia, and significantly decreased free palmitic acid, increased free oleic acid, normalized lipid profile, decreased oxidative stress, cyclin D1 expression, Ki-67 immunoreactivity, and Bcl2 expression, and increased the ratio of apoptotic/non-apoptotic cells. Mechanistically, vildagliptin elicited these physiological and molecular alterations by restoring normal AMPK signaling and reducing the cellular expressions of FASN and HMGCR, restoring AMPK-dependent phosphorylation of p53 at Ser-15 and reducing Akt/mTOR signaling. These results indicate that vildagliptin may alleviate betel-nut induced carcinogenesis in the liver of female mice. Copyright © 2020. Published by Elsevier Inc.

Citation

Moumita Nath, Kasturi Bhattacharjee, Yashmin Choudhury. Vildagliptin, a dipeptidyl peptidase-4 inhibitor, reduces betel-nut induced carcinogenesis in female mice. Life sciences. 2021 Feb 01;266:118870